Therapeutic products



Patented Aug. 5, 1952 zstazoc UNITED STATES rarest; ret el:

THERAPEUTIC PRODUCTS: Edward J. Matson, North Chicago, and Le Roy W.Clemence, Highland Park, Ill.,'

ssi ilbrs o Abbott, Laboratories, North 'OhicagpQIlIJ," a corporation ofIllinois Ne. Drew n APP iQQ-MQEQE4 135 S rial .7.353

c 1 u v t n at o. hera eut c nxeduets and includes among its objects andadvantages new. th t c em e tiens efieet ve, asiest i e s s n l d n cocesis awn;

ceee s nini ieus di rrhe eeusedby a mell. p otozo n rg sm h e lti lieseil ra i in the n e inese dis se ewljs. 3. 8 chicke sv d rke s are nownt be n ttle?! larly susceptible. For a, long time after the disease wasknown and after several species of theorganism had been specificallyidentified, it was still considered that, under ordinary circumstances.treatment of diseased birds was out of the question, and sanitation toprevent spread of the infection was the sole expedient relied on tocombat the disease.

Our invention cqmprisesamine salts of; a phenylarsonic acid of theformula where n X, is a mem er lect d. Ir ne as c ass con stin f e seaMrQxiL ami we su roups: a d amine e le edir m the. smi e consisting; oflower alkyl. lower al kanol' and mine nsh de k l-emineehe e t resultsintl etreatment of coccidiosis havebeen and, e e n X s a. haloge a omand in ar: ticular when X is in the para position. The most satisfactoryamines have been the lower-alkylglucamines, methylg lucamine inparticular; and the lower alkanolamines. such as ethanolamine inparticular; and ethylenediamine. Qf these methylglycamine has been themost satisfactory while ethanolamine is particularly suitable because ofits 'lowercost.

Maha a-me a salt of r b qmerh hy s en c acid.

BrAsHzOaQCHMH) (CH-OHhGHnNHOH;

To a solution of about 39 parts (0.2 moli'of meth l e amine in 200 r s.of Wa e there is a d wi h irr ng. 5. part 9 2 mp1). or pom ph n ar e ie,c The mixture isifi tere to r m ve a sm l m unt nso ub e. ma eria nd add t 0 p s D ne te-. 10 This mixtu is adde w th. st xri e 92 00 pa ts qf.ee iene- A mmy. sticky mass epe iesir m. whi h the 14; Claims. (01.260-442) solvents are decanted. T e gum isthen dissolved by warming in25.0 partsof methanol and the solution is filtered and the filtrateadded gradually with stirring to 1.5.00 parts of acetone. Thisprecipitates the material as a crystalline powder which is filtered andwashed with acetone and dried in vacuum to secure a yieldof 77.6 parts.The. theoretical analysis is N 2 .93%. as 15.75%. Analysis of theparticular batchrecited above EW LE Methy lglucamine salt of .pc-hlorophenylarsonic acid Approximately 13 grams (0.055 mole) ofpchlorophenylarsonic acid is added to solution of 1i grams (0.055 mole)of methylglucamine dissolved in cc. of methanol. The mixture'isdissolved by heating and stirring. The solution is filtered while hotand added to 400 cc. of acetone with constant stirring. The precipitatewhich forms tends to be gummy. The precipitate is triturated furtherwith more acetone and the solid filtered offend washed with acetone. Thepowder fdrmedisdried in avacuum drier. i-The product has amelting pointof 1-31 to 132- C.-, with decomposition. The theoretical arsenic contentfor the The analysis of the above material shows that it contains 17.91%arsenic.

EXAMPLE 3 Monoetl cnolcmmesaltof prch loroph ny arsenic acidGlQ-ASHaOaNHaGHzCHzOH Approximately 13.0 grams (0.055 mole) ofpchlorophenylarsonic acid is added with stirring to a solution of 3.4grams (0.055 mole) of monoethanolamine dissolved in 75 cc. of methanol.Solution is obtained upon warming of the mixture. The solution isfiltered and poured with stirring into 350 cc. of acetone. A whitecrystalline preipitate forms which isfiltered and washed with a eto e).his r ta l e ma e i is hen dr n a, dr er. e o u t has e el in pa t. Qt1.35 to 36 -v The h et a a e osmeticsh be ee m o nd i 25-2 ars n a d te. ana ys f the requel shows t to te 3 EXAMPLE 4 Ethylenediamine salt ofp-chlorophenylarsomc acid About 15.0 grams of (0.055 mole)p-chlorophenlyarsonic acid is added with stirring to a solution of 6.6grams (0.11 mole) of ethylenediamine' dissolved in a mixture of 50 cc.of methanol and 15 cc. of water. The mixture dissolves upon crystallineprecipitate forms, which is filtered and washed well with acetone. Afterdrying in a vacuum drier, this precipitate has a meltingpoint of withdecomposition. The theoretical arsenic content for the above compound is28.14%, and upon analysis this material is found to contain 27.81arsenic.

EXAMPLE 5 g Monoethanolam'ine salt of p-bm'mophenylarsoiiic To 12.2parts (0.2 mol) of monoethanolamine in 100 parts of methanol there isadded 56.2 parts (0.2 mol) of p-bromophenylarsonic' acid with stirringand a clear solution results on warming which is filtered a'ndthfiltrate added with stirring to 750 parts of acetone. This gives aprecipitate which is filtered oif and thoroughly Washed with acetone anddried in vacuum to secure a yield of 60.2 parts. The theoreticalanalysis for arsenic in this compound is 21.93% and analysis of thesample gives 21.97%.

V EXAMPLE 6 Monoethanolamine salt of o-chlorophenylarsonic the materialto contain 24.50% arsenic and 4.68% 60 nitrogen.

EXAMPLE 7 M onoethanolamine salt of m-chlorophenylarsonic acidp- About6.5 grams (0.028 mole) of m-chlorophenylarsonic acid is added to thesolution of 1.7 grams (0.028 mole) of monoethanolamine dis solved in 40cc. of methanolf Solution isobtained by stirring. The solution isfiltered and added dropwise with stirring to 175' cc. of acetone. Acrystalline precipitate is formed which is filtered and washed withacetone. After drying in a vacuum drier, the compound has a meltingpoint of 1323 C. The theoretical nitrogen and arsenic contents for theabove compound are 4.70% nitrogen and 25.21% arsenic. Analysis of thematerial shows that it'contain's'- f4'.8l% nitrogen and 24.75 arsenic.

EXAMPLE 8 .Methylglucamine salt of m-chlorophenylarsonic acid About 6.5grams (0.028 mole) of m-chlorophenylarsonic acid is added to a solutionof 5.5 grams (0.028 mole) of methylglucamine suspended in 40 cc. ofmethanol. Solution of the mixture is obtained by stirring and warming.The solution is, filtered and added dropwisewith stir-ring to 20000. ofacetone. The precipitate which forms is filtered oft and washed withacetone. After drying in alvacuum drier, the material has amelting pointof 1823 C., with decomposition. The theoretical nitrogen arseniccontents are 5.24% nitrogen and 17.38% arsenic. Upon'analysis, thematerial is found to contain 3.52% nitrogen -and17.01% arsenic.

' f XAMPLE 9 Ethylenediamine saltof o-chlorophenylarsom'c .-1 J,;-..acid w EXAMPLE 1o Ethylenedidntine' salt of pebmmcphenylarsonic To10.2 parts (0.17 mol) of ethylenediamine in parts of methanol, there isadded 47.7 parts (0.17 mol) of p-bromophenylarsonic acid with stirring.A solution is not obtained, even on boiling, and a test sample 'showedincomplete solubility when diluted with water. An additional 9.5 partsof ethylenediamine is added to the alcoholic suspension. This mixturedoes not result in complete solution on boiling, but a test sample did.show .completesolubility on dilution with water. I A

Thirtyrfive'parts of water arefadded to the hot alcohol mixture and aclear. solution obtained. T l'iis'solution isfiltered hot and added withstirring to'9'00 parts of acetone and a precipitate is secured. Theprecipitate is filtered and washed with acetone and dried in vacuum tosecure a yield of 45.5 parts. The theoretical analysis for acne-20oMetfiy lglucmm'ne salt of, 3-7titra-Lhydroxyphem Asolution' 'isyma'de upof I395 parts .(0.'1 5 mol) of '3-nitro 4 hydroxyphenylarsonic 'acidffih1200 parts of methanol, and the 'solutionis filtered to make it entirelyclear. A second solution is made up of 29.3 parts (0.15 mol) ofmethylglucamine and 350 parts of hot methanol. The second solution isadded quickly with stirring to the first solution and then 2,000 partsof acetone are quickly added with continued thorough stirring. Thisresults in the immediate formation of a slightly gummy precipitate whichquickly became crystallized. The mass is allowed to stand about twohours and filtered and the precipitate is washed with acetone andtransferred immediately to a vacuum desiccator and dried. There issecured a yield of 67 parts of a water soluble crystalline compound. Thetheoretical analysis for arsenic is 16.37% and test analysis of thebatch gives 16.24%.

EXAMPLE 12 M onoethanolamin-e salt of arsanilic acid 43.4 grams (0.2mole) of arsanilic acid (p-aminophenylarsonic acid) is added withstirring and heating to a solution of 12.2 grams (0.2 mole) ofmonoethanolamine in 100 cc. of methyl alcohol. The mixture is warmeduntil a clear solution is obtained. The solution is then filtered andcooled. The cold solution is added gradually with stirring to 600 cc. ofdioxane. The crystalline precipitate is filtered and washed with dioxaneand dried in a vacuum. The theoretical analysis for arsenic is 26.97%and analysis of the sample is 26.3%.

In the preparation of the alkylenediamine salts, it has been foundnecessary to add more than the theoretical amount of alkylenediamine toeffect solution. Although only one mole is theoretically required for 2moles of the phenylarsonic acid derivative, we have found it advisableto use several times the required amount of alkylenediamine. The exactnature of this phenomenon is unknown to us but presumably it isnecessary to have an excess of the diamine due to some intermediateformation. It should be noted, however, that the salt which is formed isthe salt containing two moles of the phenylarsonic acid derivative to 1mole of the alkylenediamine.

We have also found that other numerous amines will provide salts havingdesirable proper ties. For example, other alkanolamines such asn-propanolamine and n-butanolamine have proven quite satisfactory. Whenp-chlorophenylarsonic acid is used, the compounds formed are then-propanolamine salt of p-chlorophenylarsonic acid and then-butanolamine salt of p-chloro-phenylarsonic acid, respectively. Otheramino-substituted-lower-alkyl-amines may be used such asn-propylenediamine, diethylenetriamine and n-butylenediamine. Whenp-chlorophenylarsonic acid is used, the compounds formed are the npropylenedi'armneltsalti of p-chlorophenylarsonic acid,diethylenetriamine salt of p-chlorophenylarsonic: zacid'andithen-butylenedi-amine salt of p-clilprophenylarsonic acid, respectively.'Iheloweri-alkyh amines have been found satisfactory also, suchas:ethyl'amm'e,

pounds formed with p-chlorophenylarsonic:neid are the e"thylamine saltof p-chlorophenylarsonic acid,- the' ri-propylamine salt ofp-chlorophenylarsonic acid, and the n-butylamine salt of Ip-chlorophenylarsonic acid, respectively.

METHOD 'OF I Compounds of the class exemplified by the foregoingexamples are best administered to chicks by dissolving the compounds ofthe invention in the drinking water offowl or mixing it with feed. Wehave found that concentrations of between 0.0005% and 0.05% aresatisfactory for the control of coccidiosis. We have found that the mostsatisfactory and efficient concentration is that of approximately0.005%. It is also within the ambit of our invention to supply solutionsand feed in the form of compositions containing the compounds of theinvention in an inert diluent such as water, feed, or other inertdiluent. Such compositions could be supplied directly to the fowl-raiserin the concentrations indicated above. would be supplied in the form ofa tablet containing the salts of the present invention in moreconcentrated form and in an amount which could be conveniently dilutedwith a suitable amount of water.

This application is a continuation-in-part of our prior application Ser.No. 682,926, filed July 11, 1946, now abandoned.

Others may. readily adapt the invention for use under various conditionsof service by employing the features of novelty disclosed or theirequivalents. It will be obvious that the disclosure contemplates theavailability of compounds of this type for other inventions to whichthey may be applicable. As at present advised with respect to theapparent scope of our invention, we desire to claim the followingsubject matter.

We claim: I

1. An amine salt of a phenylarsonic acid of the formula I -Asfiz0s Xwhere X represents a halogen atom, said amine being selected from thegroup consisting of low- Alternately, the compounds 1' 11.:The'methyiglucamine salt of -pheny1ersonic acid. 1

pr'chloro- 12. The monoethanolamine salt of p-chlorophenylarsonic acid.

13. The vethylenediamine' salt of p-chloro- .phenyiarsonic acid.

14. The monoethanolamine salt of p -bromophenylarsonic. acid; z

, LE ROY w. CLEMENCE. *RicFEnENcEs CITED 8 UNITED STATES PATENTS NumberName Date 2,274,593 Despois Feb. 24, 1942 r 2,476,890 Morehouse' July19, 1949 FOREIGN PATENTS Number Country Date 224,764 Great Britain Nov.20, 1924

1. AN AMINE SALT OF A PHENYLARSONIC ACID OF THE FORMULA